The aim of this proposal is to develop novel mouse models that produce conditional knockout of the norepinephrine transporter (NET) gene. The overarching goal of this work is to elucidate the role of NET in central versus peripheral sympathetic nervous system (CNS vs. SNS) noradrenergic neurons to influence psychiatric phenotypes, and inspire new treatments for such disorders. Increasing evidence indicates significant comorbidities between brain and cardiovascular disorders. For example, patients with anxiety complain of heart palpitations and patients with tachycardia disorders have a higher incidence of anxiety. How these comorbidities derive from shared genetic risk factors is poorly understood. One shared component of circuits controlling mood and cardiovascular function is the neurotransmitter, norepinephrine (NE). NE released at synapses in the brain and heart is inactivated through active transport into terminals by the presynaptically- localized NET, making NET a critical mediator of NE inactivation and presynaptic catecholamine homeostasis. We have demonstrated that mice with a constitutive NET knockout or knock-in of a non-functional NET mutation, A457P, exhibit both tachycardia and anxiety. We have now generated the first mouse with a floxed NET allele to allow selective NET knockout to dissect CNS vs. SNS contributions to psychiatric disease. There has been little study to date of promoters that can drive expression in noradrenergic neurons selectively in the CNS versus SNS. This proposal will determine the ability of CRE driver lines to selectively knock out NET in central versus peripheral noradrenergic neurons. Aim I will cross CRE lines that reportedly drive recombination in either brain or SNS NE neurons with Rosa reporter mice and NET floxed mice. We will determine reporter expression, and NET expression and activity in the brain and SNS. Aim II will determine if anxiety/depression- related behaviors observed with constitutive manipulation of NET are driven by brain versus SNS NET. These studies introduce the novel scientific idea to use genetic dissection of brain versus SNS noradrenergic function, and provide a novel characterization of tools to accomplish this. These models will translate to the study of many other genes with tissue-specific expression in noradrenergic neurons. This work will allow us to more precisely understand the role of brain noradrenergic signaling in mental disorders.